Craniosynostosis (CS) refers to the premature fusion of one or more of the cranial sutures, leading to abnormal cranial and facial shapes and function. We propose to investigate the hypotheses that CS risk is associated with maternal nutrient intake and factors related to thyroid dysfunction. We propose to study intake of nutrients involved in methylation, glycemic control and oxidative stress because folate-responsive neural crest cells contribute to the development of the skull and because glycemic control and hypoxia may contribute to CS. We propose to study factors related to thyroid dysfunction because several case-only studies have reported CS among women and neonates with thyroid disorders. The contribution of the proposed exposures to CS etiologies has either not been evaluated or has largely been investigated with studies that have numerous limitations. We will address our hypotheses by accomplishing the following Specific Aims: Aim 1. Intake of nutrients. We will determine whether maternal intakes of nutrients from the diet or supplements that are involved in methylation, glycemic control or oxidative stress are associated with risk of CS among offspring, including folate/folic acid, choline, betaine, methionine, vitamin B12, vitamin B6, riboflavin, glycemic load, 2-carotene, vitamin E, and vitamin C. Aim 2. Factors related to thyroid dysfunction. We will determine whether factors that are predictive of thyroid dysfunction are associated with risk of CS among offspring, including maternal hypertension, intake of iron, race-ethnicity, age, number of previous live births, miscarriages and fetal deaths, intra-uterine growth retardation, preterm delivery, smoking, alcohol, body mass index, diabetes, use of anti-depressants, and sub-fertility. The aims will be achieved by using existing data from a large, multi-state, population-based case-control study of birth defects, the National Birth Defects Prevention Study (NBDPS), which includes high quality clinical data that were collected using rigorous case ascertainment and classification criteria and detailed data on exposures that were collected by maternal interview. The proposed research represents the first large-scale study to explore the proposed exposures and CS. This research will fill an important data gap by launching forward our knowledge regarding etiologies of CS and providing direction for the next generation of studies of CS. PUBLIC HEALTH RELEVANCE: The goal of this research program is to contribute to the prediction and prevention of craniosynostosis. The medical costs of craniosynostosis are huge and of course the emotional costs to families of the affected children are immeasurable. This proposal will improve our understanding of the causes of craniosynostosis, so that ultimately we will be able to prevent it and/or detect it as early as possible.